This invention relates to an inhibitor of heart muscule cell apoptosis, and a prophylactic and/or therapeutic agent for heart diseases.
In recent years, it has been revealed that apoptosis is closely invloved in onset or progress of various heart diseases (R. Sanders Williams, The New England Journal of Medicine, vol. 341, p. 759, 1999).
Apoptosis is closely invloved in morphognesis and histogenesis in the development process, maintenance of homeostasis, and bio-defence, and it is cell death having an important role in maintaining individual lifes. When the death process regulated by genes is congenitally or postnatally hindered, apoptosis is excessively induced or inhibited to cause functional disorders in various organs, and thus diseases (Shin Yonehara, Saishin Igaku, vol. 54, p. 825, 1999).
In a mammalian heart, it is considered that heart muscle cells are finally differentiated cells, and lose proliferation activity. Accordingly, when heart muscle cells disappear by apoptosis, the heart contraction should be maintained only by remaining cells. Disappearance of heart muscle cells beyond threshold necessary for maintaining the heart contraction would result in abnormal heart functions and diseases. Apoptosis of heart muscle cells is actually observed in various animal models with cardiac insufficiency or in human patients with cardiac insufficiency, and it is noted that disappearance or lack of heart muscle cells by apoptosis may be involved in onset and progress of cardiac insufficiency (Narula, J. et al., The New England Journal of Medicine, vol. 335, p. 1182, 1996). It is further recognized that in heart muscle cells of human patients with cardiac insufficiency, an apoptosis-inhibitory factor Bcl-2 is expressed in excess, which is a possible compensation mechanism for cardiac insufficiency (Olivetti, G. et al., The New England Journal of Medicine, vol. 336, p. 1131, 1997); that serum levels of soluble Fas (sFas has an inhibitory activity on apoptosis) which lacks a membrane penetration domain in the Fas receptor known as an apoptosis inducing receptor, are increased significantly in proportion to severeness in NYHA class (New York Heart Association Functional Class) but independently of fundamental diseases, and thus an increase in serum levels of sFas is considered to be a compensatory mechanism to inhibit promotion of apoptosis in cardiac insufficiency (Nishigaki, K. et al., Journal of the American College of Cardiology, vol. 29, p. 1214, 1997); and that in the heart with dilation-type myocardiosis, deoxyribonuclease I (DNase I) considered as a indicator of apoptosis is increased 7-fold or more than in healthy persons (Yao, M. et al., Journal of Molecular and Cell Cardiology, vol. 28, p. 95, 1996).
Recent important findings related to protection of heart muscle cells include those from studies on mice with deficiency in gp130 specifically in the ventricle. As a result of analysis of the mice, it is revealed that the signal from gp130-mediated receptors (gp130 signal) play an important role in protecting the heart functions, and these studies draw attention as a new development of heart muscle cell-protective signals leading to therapy of heart diseases (Hirota, et al., Cell, vol. 97, p. 189, 1999, and Senior, K. Molecular Medicine Today, vol. 5, p. 283, 1999). Therefore, it is highly possible that a compound having an inhibitory action on apoptosis of heart muscle cells or an enhancing action on heart muscle cell-protective signals may serves as a new preventive and/or remedy for heart diseases.
When considered at the level of internal organs, the functions of the heart muscle are lowered in human cardiac diseases, and insufficient heart muscle contraction often endangers the maintenance of the life. Abnormalities, for example, myocardial disorders, abnormal heart pumping, pressure burden due to high blood pressure, volume burden due to acute nephritis, and insufficient blood pumping caused by these abnormalities lead to the onset of cardiac insufficiency. Against these abnormalities, the sympathetic nervous system, the internal secretion system, and the like work together to start a compensating mechanism, resulting in cardiac hypertrophy accompanied by hypertrophy of myocardial cells. However, when these abnormalities occur alone or in combination persistently and chronically, the hypertrophied myocardial cells are not sufficiently supplied with blood, and thus the myocardial cells disappear due to apoptosis, etc. As a result, the compensating mechanism fails to work, leading to a cardiac insufficiency syndrome accompanied by myocardial disorders such as insufficient heart contraction, a reduction in pumped blood, circulatory disorders in internal organs, venostasis, and body fluid retention. To treat these, amelioration of myocardial cell disorders, enhancement of the heart-protecting action, recovery from the reduced cardiac functions due to insufficient heart contraction, suppression of causative breakdown of compensation in vivo, or amelioration of the excessive compensation is necessary.
Incidentally, 2-substituted-4H-1,3-benzothiazin-4-one compounds such as 2-(2-pyridyl)-1,3-benzothiazin-4-one, 2-(3-pyridyl)-1,3-benzothiazin-4-one and 2-(4-pyridyl)-1,3-benzothiazin-4-one are described in Chemical Abstracts, vol.51, 17927g (1957), but any specific action thereof is not described. 2-ethoxycarbonylmethyl-1,3-benzothiazin-4-one is described in Heterocycles, vol.22, 1677-1682 (1984), but any action thereof is not described.
At present, the cardiac insufficiency syndrome is treated by using cardiotonic glycosides such as digoxin, sympathetic agents such as dobutamine, phosphodiesterase inhibitors such as amrinone, vasodilators such as hydralazine, calcium antagonist, angiotensin converting enzyme inhibitor and angiotensin receptor antagonist, and dilated cardiomyopathy is treated by xcex2-blockers, etc. But for therapeutic methods for suppressing the excessive compensation and for suppressing breakdown of compensation including apoptosis, there are no reported pharmaceuticals entirely satisfactory in clinical use.
The present inventors found for the first time that a variety of 2-substituted-4H-1,3-benzothiazin-4-one compounds have an inhibitory action on heart muscle cell apoptosis. As a result of further investigation based on these findings, the present inventors achieved the present invention.
Thus, the present invention provides:
(1) An inhibitor of heart muscle cell apoptosis comprising a compound represented by the following formula: 
wherein R represents an optionally substituted hydrocarbon group, an optionally substituted aromatic heterocyclic group, or an optionally substituted amino group; or a salt thereof (referred to as Compound (I));
(2) The inhibitor of heart muscle cell apoptosis as described in (1), which is a prophylactic and/or therapeutic agent for heart diseases;
(3) The inhibitor of heart muscle cell apoptosis as described in (1), which is an enhancer of gp130 signal;
(4) The inhibitor of heart muscle cell apoptosis as described in (1), which is an enhancer of heart muscle cell protection signal;
(5) A pharmaceutical composition comprising Compound (I);
(6) A method for inhibiting heart muscle cell apoptosis in a mammal, comprising administrating an effective amount of Compound (I) to said mammal;
(7) Compound (I) which is used for inhibition of heart muscle cell apoptosis;
(8) Use of Compound (I) for production of an inhibitor of heart muscle cell apoptosis.